Mineral compositions are commonly taken as dietary aids, either as therapeutic preparations directed to a specific medical problem or as general nutritional supplements. Among useful dietary supplements are dosage units of calcium citrate, orally administered in solid or liquid form (U.S. Pat. Nos. 4,772,467, 4,814,177, and 4,851,221; each patent herein incorporated by reference). Oral administration of calcium citrate as a nutritional supplement both modestly increases levels of urinary citrate and provides bioavailable calcium. By modestly increasing levels of urinary citrate, administration of calcium citrate counters calcium nephrolithiasis (i.e., formation of calcium-containing kidney stones). Furthermore, calcium is more readily absorded when administered as calcium citrate than as calcium carbonate, i.e., the administration of calcium citrate provides calcium that is more bioavailable. Improved absorption of calcium allows more effective treatment of calcium-deficiency conditions like osteoporosis.
Osteoporosis--a condition in which an affected person's bones become increasingly porous, brittle, and subject to fracture, owing to loss of calcium and other mineral components--is common in older persons, particularly in postmenopausal women. Bone loss may also be associated with a variety of other conditions, including those brought on by long-term steroid therapy and certain endocrine disorders. If not countered, osteoporosis or bone loss may lead to fractures of the spine, hip, and long bones.
Certain drugs that block bone destruction may help avert the progression of postmenopausal osteoporosis. The most potent of these drugs are found among a class of synthetic compounds called bisphosphonates. Alendronate (4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid), which is approved by the Food and Drug Administration (FDA) for treatment of osteoporosis, has been shown to produce a transient increase in spine and hip bone density, as well as to reduce spinal fractures. Alendronate's long-term effects are not known, however, and it may cause esophageal ulcers. Estrogen replacement therapy has shown effectiveness in countering postmenopausal osteoporosis. However, estrogen may increase the risk of breast cancer, and may cause discomforting side effects, such as vaginal bleeding, if it is given intermittently with progesterone, which is usually recommended. Estrogen analogs may overcome some of the side effects of estrogen, but cause others, such as hot flashes and blood clots.
Intake of calcium offers potentially a safer and more natural means of averting postmenopausal osteoporosis. Both the FDA and the National Institutes of Health have endorsed adequate intake of calcium as a means of countering the bone loss that occurs with menopause in women, and with aging in both men and women.
Calcium's action in countering bone loss has been ascribed to its ability to suppress secretion of parathyroid hormone (PTH), a hormone that stimulates bone resorption or destruction (e.g., see McKane, WR et al., 1996, J. Clin. Endocrin. & Metab. 81:1699-1703). Moreover, calcium ensures adequate mineralization of bone by providing an essential component of bone. The average weight percent of calcium in the human body is approximately 1.4, and approximately 99 percent of calcium in the human body is found in skeletal structures. Consistent with these facts, supplementation of the diet with calcium can be an important element of preventing and treating osteoporosis, as well as bone loss associated with other pathologies, such as chronic diarrheal syndrome. Supplementation of diet with calcium may also be an important element of treating other conditions, including hypoparathyroidism, renal osteodystrophy, hypertension, and phosphate accumulation in chronic renal failure.
The use of dietary supplements that provide calcium, however, has limitations. For example, the amount of calcium absorbed from supplements taken daily tends to decline with time (e.g., see Sakaee et al., 1994, J. Urology 152:324-27). In addition, intake of additional calcium may promote the formation of calcium-containing kidney stones. The risk of such kidney-stone formation (i.e., calcium nephrolithiasis) may be particularly high in patients with hypercalciuria, especially when the hypercalciuria results because of excess calcium absorption from the gastrointestinal (GI) tract (as in absorptive hypercalciuria).
The chemical form in which dietary calcium supplements are administered is of consequence for their capacity to provide bioavailable calcium as well as their propensity to promote kidney-stone formation. As noted previously, when calcium is orally administered as calcium citrate, calcium absorption is greater than when calcium is administered as calcium carbonate (e.g., see Harvey et al., 1990, J. Am. Coll. of Nutr., 9(6):583-587; Dawson-Hughes et al., 1990, N. Eng. J. Med. 223:878-83). Not only is calcium more bioavailable when administered as calcium citrate, calcium-citrate administration also has a mild citraturic effect. Administration of calcium as calcium citrate modestly increases the level of urinary citrate, which retards formation of kidney stones (Harvey et al., 1985, J. Clin. Endocrin. & Metab. 61:1223-25).
However, supplements other than calcium citrate have greater citraturic effects, including, in order of increasing effectiveness, potassium bicarbonate, potassium citrate, and magnesium potassium citrate. U.S. Pat. Nos. 4,895,980, 4,985,593, 5,219,889 and 5,432,200 (each incorporated herein by reference) relate to compositions of, as well as to methods for making and using, magnesium potassium citrate.
In studies comparing citraturic effects of potassium citrate and potassium bicarbonate, potassium citrate has been shown to produce more prominent levels of urinary citrate than equivalent amounts of potassium bicarbonate (Sakhaee, K. et al., 1992, J. Urology, 147:975-976). While the citraturic action of potassium citrate was attributable mostly to its delivery of alkali load, its citraturic action also resulted from renal excretion of absorbed citrate escaping in vivo metabolism. Consequently, oral administration of potassium bicarbonate, because it also delivered alkali load, also had a citraturic effect, but less than that of potassium citrate.
Delivering alkali load is not only a mechanism for inducing a citraturic effect, but it also represents an additional mechanism for countering bone loss (Sebastian A. et al., 1994, N. Eng. J. Med., 330:1776-1781). Thus, potassium citrate, for example, may be administered not only to provide a citraturic effect to counter formation of kidney stones, but also independently to counter bone loss by delivering alkali load. Delivering alkali load counters bone loss by partly compensating for the cumulative buffering effect that skeletal sources provide against diet-dependent acid production (Sebastian A. et al., 1994, N. Eng. J. Med., 330:1776-1781). Age-related reductions in bone mass appear to result at least in part from this cumulative buffering effect. In postmenopausal women, for example, the oral administration of potassium bicarbonate at a dose sufficient to deliver alkali load improves calcium and phosphorus balance, and appears both to reduce bone resorption and to increase the rate of bone formation. As another example, oral administration of potassium bicarbonate, but apparently not sodium bicarbonate, also reduces urinary calcium excretion and improves calcium balance in healthy men (Lemann et al., 1989, Kidney Int'l 135:688-695).
Contrasting the calcium-balance effects of potassium bicarbonate with those of sodium bicarbonate indicates that potassium alone, independent of bicarbonate, may trigger a reduction urinary calcium excretion. Consequently, while preliminary in nature, these results indicate that the provision of potassium itself may have a role in countering kidney-stone formation by reducing urinary calcium excretion.
Use of a dietary supplement consisting essentially of calcium and citrate has been recognized both to provide calcium and, as an ancillary benefit, to deliver a small or modest level of alkali load (U.S. Pat. No. 4,851,221, previously incorporated by reference). However, since the alkali load level delivered by a dietary supplement like a calcium citrate generally correlates with cations absorbed, and since absorption of calcium cations from a dietary supplement like a calcium citrate may be relatively small, the alkali load level delivered by a dietary supplement consisting essentially of calcium and citrate is relatively quite modest. Furthermore, since absorption of calcium cations may be attenuated over time, the alkali load level delivered by a dietary supplement consisting essentially of calcium and citrate also may be attenuated over time.
A mineral composition comprising magnesium potassium citrate in a single salt (having a molar ratio of magnesium to potassium to citrate of 1:4:2, respectively) is useful as a dietary supplement to overcome certain renal losses of magnesium and potassium, as well as to increase urinary excretion of electrolytes (U.S. Pat. Nos. 4,895,980, 4,985,593, 5,219,889, and 5,432,200; each previously incorporated by reference). While the mineral composition comprising magnesium potassium citrate in a single salt delivers, as a dietary supplement, a significant level of alkali load, it is not a source of calcium. Furthermore, while the mineral composition provides magnesium, magnesium neither suppresses secretion of PTH nor ensures adequate mineralization of bone. In general, magnesium is not a physiological substitute for calcium. A mineral composition, amenable for administration as a dietary supplement, that simultaneously provides bioavailable calcium and delivers a more-than-modest level of alkali load, while countering kidney-stone formation, is desirable.
ABBREVIATIONS DPD: deoxypyridinoline FDA: Food and Drug Administration GF: glomerular filtrate GI: gastrointestinal meq: milliequivalents mmol: millimoles PCC: potassium calcium citrate PTH: parathyroid hormone